Lipid vesicles can function as carriers for bioactive agents. However, the utility of lipid vesicles as long circulating carriers has been limited by the general fragility of liposomes with regard to binding and lysis by serum proteins. Previous studies on polymerization-stabilization of lipid vesicles have utilized alkene or diacetylene polymerization in the headgroup or lipid anchor region. Due to the concomitant changes in lipid and headgroup packing, these methods yield lipid membranes with significantly non-native properties such as increased permeability and decreased fluidity.
More recently, membrane-anchored polyacrylates have been added to pre-formed vesicles and cross-linked in situ by EDC and a diamino linker, yielding a protected, polyanionic liposome. High negative surface charge limits carriers of this type for scavenging uptake mechanisms in vivo rather than circulation. Moreover, a synthetic limitation arises due to the requirement for post-crosslinking purification.
Surface neutral polymer-protected “stealth” vesicles function as long-circulating carriers and have been successfully implemented as drug carriers, featuring singly-anchored polyethylene glycol chains (PEG). The incorporation of lipid-anchored PEG into lipid vesicle membranes blocks serum proteins from binding to the vesicle, thus preventing lipid extraction, opsonization, and immunoclearance. However, PEG lipid vesicles do not tolerate dehydration and thus are not useful for long-term anhydrous storage of therapeutic agents included with the lipid vesicle.
Trehalose is a naturally occurring disaccharide of glucose with 1,1(α, α′) linkage that protects biomembranes from desiccation and has been implicated as a key factor in the survival of microorganisms under anhydrobiotic conditions. Recent reports have documented the ability of both free trehalose and membrane-anchored trehalose, such as microbial trehalose mycolate (TDM) and its synthetic analog trehalose dibehenate (TDB), to protect and maintain the physical properties of synthetic supported lipid membranes. It has been further demonstrated that trehalose-functionalization can effectively block non-specific surface binding of serum proteins to trehalose-polymers. However, the previously used anchored trehalose compounds do not allow for the control or tuning of the stability of the lipid vesicle at the linkers used therein to meet specific operational requirements, such as acid sensitivity.